The role of gut microbiota in host responses to cancer immunotherapy

The role of gut microbiota in host responses to cancer immunotherapy

A recent commentary in Nature Reviews Gastroenterology & Hepatology, written by Dr. Susan E. Erdman from the Division of Comparative Medicine at the Massachusetts Institute of Technology in Cambridge (USA), has covered the role of microbial strategies in cancer prevention and remission. Dr. Erdman refers to a study by Vetizou et al. that revealed that the gut microbiota modulates host responses to cancer immunotherapy. It demonstrated that the antitumour efficacy of the cytotoxic T-lymphocyte protein 4 (CTLA-4) blockade is influenced by gut microbiota composition. Based on animal models and samples from patients undergoing immunotherapy for malignant melanoma or non-small cell lung carcinoma, the researchers showed that certain Bacteroides spp. are critical for therapeutic success against the cancer target. Ipilimumab, a human monoclonal antibody directed against CTLA-4, can modify the abundance of immunogenic Bacteroides spp. in the gut, which in turn affects its anticancer efficacy. CTLA-4 blockade stimulated a biased interleukin 12 (IL-12)-dependent type 1 T helper cell and T regulatory T cell response that favoured certain bacterial populations (Bacteroides fragilis and/or B. thetaiotaomicron and Burkholderiales), which facilitate tumour control in mice and patients while sparing intestinal integrity. A previous pilot study demonstrated that a restricted microbiota, free of known pathogens and harbouring relatively few bacterial species dominated by unclassified Bacteroidetes, has onco-protective effects in mice. These studies suggest that beyond immunotherapy, directing such host immune biases emerges as a future challenge for cancer therapy. However, research in humans is needed in order to elucidate whether including resident microbes or synthetic microbe cocktails (“anticancer probiotics”), such as B. fragilis, would be the best strategy for stimulating beneficial antitumour immunity beyond the check-point blockade. All together, these data have implications not only for cancer immunotherapy, but also for novel approaches using microbial strategies in cancer prevention and treatment.

 

In the same line, a recent review by Dr. Scott Bultman from the Department of Genetics and Lineberger Comprehensive Cancer Centre at University of North Carolina at Chapel Hill (USA) suggested that some of the interindividual variation observed in epidemiology and intervention studies that have investigated mechanisms by which commensal microbiota protect against cancer might be explained by differences in microbiota among the participants. As butyrate-producing bacteria and soluble or “fermentable” fibre can both increase levels of butyrate (a well-established histone deacetylase [HDAC] inhibitor that is a tumour-suppressive metabolite in mice), both of these are hypothesized to be useful in chemoprevention. Besides, butyrate bioavailability appears to be restricted to the colon; butyrate is a naturally occurring fatty acid that could target tumour cells in the colonic crypt because of the Warburg effect and avoid adverse effects in other tissues when compared to chemotherapy drugs. However, butyrate and fibre-related effects as causal factors in chemoprevention need to be confirmed.

 

Microbial strategies may not only be used in cancer prevention and treatment, but also in predicting chemotherapy-related bloodstream infection. A recent study, led by Dr. Dan Knights from the Department of Computer Science and Engineering and BioTechnology Institute at University of Minnesota in Minneapolis (USA), has suggested that the gut microbiota may be a useful tool in identifying high-risk patients before hematopoietic stem cell transplantation (HSCT). The researchers collected faecal samples from 28 patients with non-Hodgkin lymphoma (NHL) undergoing allogeneic HSCT prior to administration of chemotherapy and quantified bacterial taxa and microbial biomarkers that predicted the risk of bloodstream infection (BSI). Analysis of faecal samples collected prior to chemotherapy showed differences between faecal samples of patients who did or did not develop BSI. Decreased diversity in pre-chemotherapy faecal samples was associated with subsequent BSI and thus may predict BSI. This suggests patients at high risk of infection prior to chemotherapy may be identified using their microbiota. Barnesiella and Ruminococceae were found to be protective against BSI. In addition, based on the relative abundance of the differentiated taxa in samples collected prior to treatment in patients who developed subsequent BSI and patients who did not develop BSI, the researchers developed a novel microbiome-based BSI risk index that predicts BSI. They also tested the individual ability of these microbes to discriminate between patients who did and did not develop subsequent BSI, finding a sensitivity of 90% at a specificity of 90%. These results demonstrate that there is a predictive association between pre-chemotherapy gut microbiome and future risk of BSI in patients with NHL receiving allogeneic transplantation. It opens a new door to the possibility of manipulating the gut microbiota to decrease risk of infectious complications in high-risk patients.

 

To sum up, gut microbes could influence cancer outcomes through their interaction with host immunity. Manipulating gut microbiota for cancer prevention and remission could be plausible strategy, and is a topic for future research.

 

 

 

References:

Bultman SJ. The microbiome and its potential as a cancer preventive intervention. Semin Oncol. 2016; 43(1):97-106.

Cheema AK, Maier I, Dowdy T, et al. Chemopreventive metabolites are correlated with a change in intestinal microbiota measured in A-T mice and decreased carcinogenesis. PLoS One. 2016; 11(4):e0151190. doi:10.1371/journal.pone.0151190.

Erdman SE. Gut microbiota: Microbes offer engineering strategies to combat cancer. Nat Rev Gastroenterol Hepatol. 2016;13(3):125-6.

Montassier E, Al-Ghalith GA, Ward T, et al. Pretreatment gut microbiome predicts chemotherapy-related bloodstream infection. Genome Med. 2016;8(1):49.

Vétizou M, Pitt JM, Daillère R, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015;350(6264):1079-84.

Andreu Prados
Andreu Prados
Andreu Prados holds a Bachelor of Science Degree in Pharmacy & Human Nutrition and Dietetics. Science writer specialised in gut microbiota and probiotics, working also as lecturer and consultant in nutrition and healthcare. Follow Andreu on Twitter @andreuprados